Abstract
Abstract Background and Aims: Smoking and pancreatitis are two major risk factors for pancreatic cancer. We developed novel mouse models of pancreatic cancer induced by smoking and chronic pancreatitis. We used two pancreatic cancer mouse models induced by overexpression of Kras with two different degrees of disease complexity. Methods: Wild type (WT), EL-Kras and Pdx1-Cre;LSL-Kras transgenic mice were subjected to a major cigarette smoke compound nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) at doses close to those accumulated with smoking (100mg/kg) or exposed to tobacco smoke (80mg/m3) in tobacco smoke chambers for five days a week during 6 weeks. Standard model of chronic pancreatitis induced by cerulein injections (50μg/kg) for 3 weeks was applied to WT and Pdx1-Cre;LSL-Kras mice. Mice were then sacrificed and pancreatic tissue analyzed. Apoptosis was assessed by TUNEL. Autophagy was assessed by measuring autophagic markers LC3-II and p62. Pancreatic lesions, proliferation, fibrosis and inflammation were analyzed by immunohistochemistry. Epithelial to mesenchymal transition (EMT) and expression of stem cell markers were analyzed by Western. Results: NNK and exposure to tobacco smoke significantly increased the number and stage of pancreatic neoplastic (PanIN) lesions in Kras transgenic mice. Smoking stimulated fibrosis and stellate cells activation but had no significant effect on inflammation. EMT markers (decrease in E-Cadherin and increase in vimentin protein levels) were stimulated by NNK and tobacco smoke exposure in both WT and transgenic mice. NNK decreased apoptosis and LC3-II level in Kras mice. In addition, smoking stimulated expression of stem cell markers sox2 and CD133. Cerulein stimulated fibrosis, stellate cells activation, inflammation, and slightly stimulated EMT in WT and transgenic mice. Combination of smoking and cerulein had additive effect on stimulation of PanIN lesion formation, fibrosis, EMT and stem cell markers induction. Conclusion: The results indicate that both tobacco smoke and chronic cerulein pancreatitis promote pancreatic cancer progression in both EL-Kras and Pdx1-Cre;LSL-Kras mice models. Smoking acts through enhancing fibrosis and EMT; whereas pancreatitis stimulates mainly inflammation and fibrosis. Smoking and pancreatitis have additive effect on fibrosis, EMT and acquiring of stem cell characteristics. Citation Format: Shiping Xu, Paul J. Grippo, Oxana M. Khayrutdinova, Samuel W. French, Stephen J. Pandol, Anna S. Gukovskaya, Mouad Edderkaoui. Novel animal models of pancreatic cancer induced by smoking and chronic pancreatitis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2730. doi:10.1158/1538-7445.AM2013-2730
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